Denaturation and solvent effect on the conformation and fibril formation of TGFBIp.
Transforming growth factor beta-induced protein (TGFBIp) aggregates into the phenotypic amyloid fibrils and/or non-amyloid deposits in corneal dystrophies and other disorders. While significant progress has been made in molecular genetics to successfully establish the link between the missense mutations of TGFBI and TGFBIp-related corneal dystrophies, the underlying mechanism for the abnormal aggregation remains elusive due to the lack of insights into the conformational perturbations induced by mutations. In the present study, we examined the effects of denaturants and a co-solvent on recombinant TGFBIp, with a focus on protein conformational changes and amyloid fibril formation. Recombinant TGFBIp was subjected to various spectroscopic studies, such as far-ultraviolet circular dichroism (far-UV CD), intrinsic tryptophan fluorescence and quenching, and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence, under various denaturing conditions (urea and guanidine hydrochloride [GndHCl], acidic pH, and trifluoroethanol [TFE, co-solvent]). A thioflavin T (ThT) fluorescence assay was used to determine the fibril formation of TGFBIp. In addition, a rabbit polyclonal antibody against the oligomer precursors that initiate the formation of amyloid fibrils was also used in dot blot experiments to detect the formation of prefibrillar precursors. The purified recombinant TGFBIp is in the folded state according to its intrinsic tryptophan fluorescence analyses. A single-step unfolding process was observed in the GndHCl denaturation experiment. Results from far-UV CD, intrinsic tryptophan fluorescence, and ANS fluorescence experiments showed that TFE exerted its solvent effects by initially unfolding and transforming TGFBIp to a beta-sheet-enriched conformer at 20%. When increased to 40%, TFE changed TGFBIp into a non-native alpha-helix conformer. Although GndHCl and TFE led to protein unfolding, enhanced fibril formation could only be observed in the presence of TFE and at acidic pH, according to the ThT fluorescence assays. The paradigmatic protofibrillar TGFBIp oligomers were also detected during the fibril formation by the dot blot experiment. Our results suggest that protein unfolding may serve as the prerequisite but is not sufficient for the fibrillogenesis. Other factors, such as the solvent used, fragmentation, or pH, may also be crucial for the formation of TGFBIp fibrils.


Quantifying climate sensitivity and climate-driven change in North American amphibian communities.
Changing climate will impact species' ranges only when environmental variability directly impacts the demography of local populations. However, measurement of demographic responses to climate change has largely been limited to single species and locations. Here we show that amphibian communities are responsive to climatic variability, using >500,000 time-series observations for 81 species across 86 North American study areas. The effect of climate on local colonization and persistence probabilities varies among eco-regions and depends on local climate, species life-histories, and taxonomic classification. We found that local species richness is most sensitive to changes in water availability during breeding and changes in winter conditions. Based on the relationships we measure, recent changes in climate cannot explain why local species richness of North American amphibians has rapidly declined. However, changing climate does explain why some populations are declining faster than others. Our results provide important insights into how amphibians respond to climate and a general framework for measuring climate impacts on species richness.


[Qualitative and quantitative descriptions of the mechanisms of action of the angioplasty balloon on coronary stenosis. An endovascular ultrasonic study].
The barotrauma induced by inflation of the balloon on an obstructive atherosclerotic plaque induces several distinct, complex effects. The object of this study was to describe these mechanisms based on endovascular echographic sections of coronary stenoses before and after balloon angioplasty. The 32 lesions analysed were richly cellular (81.2%) and associated with calcifications in 31% of cases. The remodelling index before angioplasty was used to individualize a majority of lesions with chronic arterial constriction (56.2%). The modelling of the plaque (dilatation or constriction) had no effect on the final luminal result. Global analysis of the endoluminal gain (4.38 +/- 2.28 mm2) showed that it was mainly due to reduction of plaque surface (78.2% of gain) without prejudging the mechanism, and less due to expansion of the global arterial surface (21.8% of the gain). The type of remodelling affected the mechanisms of action of balloon angioplasty. Dissection was present in 53.1% of cases. Fragmentation of the plaque with embolisation is a common phenomenon (28% of cases). The authors conclude that there are four mechanisms which coexist: 1) Reduction of plaque thickness cannot physically correspond to simple compression of tissue. The plaque is redistributed longitudinally. 2) Arterial expansion only plays a minor part in endoluminal gain. 3) Plaque rupture is directly related to the acute increase in wall stress often exceeding the thresholds of rupture of its components. Finally, 4) embolisation by parietal fragmentation, a mechanism often unknown or ignored which plays an essential part in the potentially deleterious effects.


Reproducibility of tear meniscus measurement by Fourier-domain optical coherence tomography: a pilot study.
To study the reproducibility of tear meniscus measurement with high-speed high-resolution Fourier-domain optical coherence tomography (FD-OCT). Twenty normal participants were enrolled in this prospective study. The lower tear meniscus in the right eye of each subject was imaged by vertical scans centered on the inferior cornea and the lower eyelid using an FD-OCT system (RTVue; Optovue, Inc., Fremont, CA) with a corneal adaptor. The system performs 26,000 axial scans per second and has a 5-micron axial resolution. Each subject was examined at two visits 30 to 60 days apart. Each eye was scanned twice on each visit. The scans were taken 2 seconds after a blink. The lower meniscus height, depth, and cornea-meniscus angle were measured with a computer caliper. The cross-sectional area was calculated using a two-triangle approximation. The between-visits coefficient of variation was 17.5%, 18.0%, 35.5%, and 12.2% for meniscus height, depth, area, and angle, respectively. The intraclass correlations for these parameters were 0.605, 0.558, 0.567, and 0.367, respectively. FD-OCT measures lower tear meniscus dimensions and area with higher between-visits reproducibility than previous OCT instruments. FD-OCT may be a useful way to measure dry eye severity and treatment effectiveness.


Onset of flowering and climate variability in an alpine landscape: a 10-year study from Swedish Lapland.
Long-term studies on phenology are rarely reported from arctic and alpine areas, but are essential for understanding biotic and abiotic controls on flowering. We monitored first flowering day (FFD) for 144 species in a subarctic-alpine area in Swedish Lapland over a period of 10 yr (1992-2001). Temperature and global radiation were monitored continuously, and snowcover duration was observed. Thawing degree-days and snowcover duration (exposure) were the dominant environmental controls on phenology. We introduce a lability index (LI) to describe the interannual variability in FFD among species. The temporal sequence of species is very constant among years, although a few species are more labile. The species were also classified into the catagories "Functional type," "Raunkiær's life form," and "Sørensen's wintering floral type." The last two reflected the environmental data best, and together with "Exposure" they were combined into a phenology index (PI). The index was subsequently used in a triangular ordination together with FFD. The ordination illustrates whether species flower earlier or later than expected from their preconditions. We hypothesize that species having a delayed flowering respond more readily to global warming than species having an already optimized flowering.


Establishing a practice based primary care research network. The University Family Practice Network in South Australia.
Practice based research networks enable the study of primary care problems in a primary care setting. To be successful, our experience indicates that a network will need to incorporate a number of key components. In South Australia, a University Family Practice Network has been established to undertake primary health care research and teaching and to contribute to the general practice workforce. The University Family Practice Network is composed of five practices and is managed jointly by the Department of General Practice, Adelaide University and the South Australian Centre for Rural and Remote Health, Adelaide University and the University of South Australia. This article details the successful establishment of the University Family Practice Network in the hope of providing a model for other universities who may be interested in setting up a practice based research network. The characteristics of this network include fractional academic positions for general practitioners, computerised medical records, location in rural and urban sites, regular meetings and the appointment of a research fellow. A number of benefits have arisen since the network's establishment that will assist its future development and sustainability. These include collocation with allied health services, development of local expertise and workforce support.


Mortality rates at 10 years after metal-on-metal hip resurfacing compared with total hip replacement in England: retrospective cohort analysis of hospital episode statistics.
To compare 10 year mortality rates among patients undergoing metal-on-metal hip resurfacing and total hip replacement in England. Retrospective cohort study. English hospital episode statistics database linked to mortality records from the Office for National Statistics. All adults who underwent primary elective hip replacement for osteoarthritis from April 1999 to March 2012. The exposure of interest was prosthesis type: cemented total hip replacement, uncemented total hip replacement, and metal-on-metal hip resurfacing. Confounding variables included age, sex, Charlson comorbidity index, rurality, area deprivation, surgical volume, and year of operation. All cause mortality. Propensity score matching was used to minimise confounding by indication. Kaplan-Meier plots estimated the probability of survival up to 10 years after surgery. Multilevel Cox regression modelling, stratified on matched sets, described the association between prosthesis type and time to death, accounting for variation across hospital trusts. 7437 patients undergoing metal-on-metal hip resurfacing were matched to 22,311 undergoing cemented total hip replacement; 8101 patients undergoing metal-on-metal hip resurfacing were matched to 24,303 undergoing uncemented total hip replacement. 10 year rates of cumulative mortality were 271 (3.6%) for metal-on-metal hip resurfacing versus 1363 (6.1%) for cemented total hip replacement, and 239 (3.0%) for metal-on-metal hip resurfacing versus 999 (4.1%) for uncemented total hip replacement. Patients undergoing metal-on-metal hip resurfacing had an increased survival probability (hazard ratio 0.51 (95% confidence interval 0.45 to 0.59) for cemented hip replacement; 0.55 (0.47 to 0.65) for uncemented hip replacement). There was no evidence for an interaction with age or sex. Patients with hip osteoarthritis undergoing metal-on-metal hip resurfacing have reduced mortality in the long term compared with those undergoing cemented or uncemented total hip replacement. This difference persisted after extensive adjustment for confounding factors available in our data. The study results can be applied to matched populations, which exclude patients who are very old and have had complex total hip replacements. Although residual confounding is possible, the observed effect size is large. These findings require validation in external cohorts and randomised clinical trials.


Sound field separation technique based on equivalent source method and its application in nearfield acoustic holography.
A technique for separating sound fields using two closely spaced parallel measurement surfaces and based on equivalent source method is proposed. The method can separate wave components crossing two measurement surfaces in opposite directions, which makes nearfield acoustic holography (NAH) applications in a field where there exist sources on the two sides of the hologram surface, in a reverberant field or in a scattered field, possible. The method is flexible in applications, simple in computation, and very easy to implement. The measurement surfaces can be arbitrarily shaped, and they are not restricted to be regular as in the traditional field separation technique. And, because the method performs field separation calculations directly in the spatial domain-not in the wave number domain--it avoids the errors and limitations (the window effects, etc.) associated with the traditional field separation technique based on the spatial Fourier transform method. In the paper, a theoretical description is first given, and the performance of the proposed field separation technique and its application in NAH are then evaluated through experiments.


Phrenic Nerve Palsy and Regional Anesthesia for Shoulder Surgery: Anatomical, Physiologic, and Clinical Considerations.
Regional anesthesia has an established role in providing perioperative analgesia for shoulder surgery. However, phrenic nerve palsy is a significant complication that potentially limits the use of regional anesthesia, particularly in high-risk patients. The authors describe the anatomical, physiologic, and clinical principles relevant to phrenic nerve palsy in this context. They also present a comprehensive review of the strategies for reducing phrenic nerve palsy and its clinical impact while ensuring adequate analgesia for shoulder surgery. The most important of these include limiting local anesthetic dose and injection volume and performing the injection further away from the C5-C6 nerve roots. Targeting peripheral nerves supplying the shoulder, such as the suprascapular and axillary nerves, may be an effective alternative to brachial plexus blockade in selected patients. The optimal regional anesthetic approach in shoulder surgery should be tailored to individual patients based on comorbidities, type of surgery, and the principles described in this article.


Translating research evidence into practice to reduce health disparities: a social determinants approach.
Translating research evidence to reduce health disparities has emerged as a global priority. The 2008 World Health Organization Commission on Social Determinants of Health recently urged that gaps in health attributable to political, social, and economic factors should be closed in a generation. Achieving this goal requires a social determinants approach to create public health systems that translate efficacy documented by research into effectiveness in the community. We review the scope, definitions, and framing of health disparities and explore local, national, and global programs that address specific health disparities. Such efforts translate research evidence into real-world settings and harness collaborative social action for broad-scale, sustainable change.


Micro-costing diagnostics in oncology: from single-gene testing to whole- genome sequencing.
Purpose: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole-genome sequencing (WGS)-based treatment selection is expected to rapidly increase worldwide. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC), and gastrointestinal stromal tumor (GIST) in the Netherlands.Methods: The activity-based costing (ABC) method was conducted to calculate total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch-centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs, and operational costs.Results: The total cost per cancer patient per technique varied from € 58 (Sanger sequencing, three amplicons) to € 2925 (paired tumor-normal WGS). The operational costs accounted for the vast majority (over 90%) of the total per cancer patient technique costs.Conclusion: This study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC, and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making.


Emulsification of silicone oil and eye movements.
Emulsification is an inherent problem of silicone oil used in vitreoretinal surgery. It has been shown that silicone oil can be made more resistant to emulsification and easier to inject by adding high-molecular-weight components (5% or 10% 423-kDa polydimethylsiloxane [PDMS]) to normal 1000 mPa · s silicone oil. The authors hypothesize that this might also reduce the movement of oil within an eye. A model eye chamber made of surface-modified poly(methyl methacrylate) was driven by a computer and a stepper motor to mimic saccadic eye movement. Seven silicone oils with different shear and extensional viscosities were tested. Two sets of eye movements were used: (amplitude 9°, angular velocity 390°/s, duration 50 ms) and (amplitude 90 °, angular velocity 360°/s, duration 300 ms). The movements were captured and analyzed by video recording. The angular velocity of an oil bubble relative to the eye chamber appears to form an exponential relationship with its shear viscosity. Depending on the thickness of the film of aqueous between the eye wall and the oil bubble, the shear rate was estimated to be between 6 and 14 × 10(4) s(-1). The addition of 10% of 423-kDa PDMS to 1000 mPa · s silicone oil significantly reduced the peak relative velocity compared with the base oil of 1000 mPa · s but not 5000 mPa · s. The addition of high molecular components to a base oil increases its extensional and shear viscosity. Although the extensional viscosity affected the ease with which the oil could be injected, the results showed that it was the shear viscosity that determined the relative velocity between the oil and the wall of the vitreous cavity, and thus the propensity to emulsify.


Structural basis for the inhibition of Polo-like kinase 1.
Polo-like kinase 1 (PLK1) is a master regulator of mitosis and is considered a potential drug target for cancer therapy. PLK1 is characterized by an N-terminal kinase domain (KD) and a C-terminal Polo-box domain (PBD). The KD and PBD are mutually inhibited, but the molecular mechanisms of the autoinhibition remain unclear. Here we report the 2.3-Å crystal structure of the complex of the Danio rerio KD and PBD together with a PBD-binding motif of Drosophila melanogaster microtubule-associated protein 205 (Map205(PBM)). The structure reveals that the PBD binds and rigidifies the hinge region of the KD in a distinct conformation from that of the phosphopeptide-bound PBD. This structure provides a framework for understanding the autoinhibitory mechanisms of PLK1 and also sheds light on the activation mechanisms of PLK1 by phosphorylation or phosphopeptide binding.


Effect of TiO2 nanoparticles and UV radiation on extracellular enzyme activity of intact heterotrophic biofilms.
When introduced into the aquatic environment, TiO2 NP are likely to settle from the water column, which results in increased exposure of benthic communities. Here, we show that the activity of two extracellular enzymes of intact heterotrophic biofilms, β-glucosidase (carbon-cycling) and l-leucin aminopeptidase (nitrogen-cycling), was reduced following exposure to surface functionalized TiO2 NP and UV radiation, depending on the particles' coating. This reduction was partially linked to ROS production. Alkaline phosphatase (phosphorus-cycling) activity was not affected, however in contrast, an alkaline phosphatase isolated from E. coli was strongly inhibited at lower concentrations of TiO2 NP than the intact biofilms. These results indicate that enzymes present in the biofilm matrix are partly protected against exposure to TiO2 NP and UV radiation. Impairment of extracellular enzymes which mediate the uptake of nutrients from water may affect ecosystem function.


Obesity, inflammation and the immune system.
Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications.


Extending the school grounds?--Bullying experiences in cyberspace.
Bullying is a national public health problem affecting millions of students. With the rapid increase in electronic or online communication, bullying is no longer limited to schools. The goal of the current investigation was to examine the overlap among targets of, and the similarities between, online and in-school bullying among Internet-using adolescents. Additionally, a number of common assumptions regarding online or cyberbullying were tested. An anonymous Web-based survey was conducted with one thousand four hundred fifty-four 12- to 17-year-old youth. Within the past year, 72% of respondents reported at least 1 online incident of bullying, 85% of whom also experienced bullying in school. The most frequent forms of online and in-school bullying involved name-calling or insults, and the online incidents most typically took place through instant messaging. When controlling for Internet use, repeated school-based bullying experiences increased the likelihood of repeated cyberbullying more than the use of any particular electronic communication tool. About two thirds of cyberbullying victims reported knowing their perpetrators, and half of them knew the bully from school. Both in-school and online bullying experiences were independently associated with increased social anxiety. Ninety percent of the sample reported they do not tell an adult about cyberbullying, and only a minority of participants had used digital tools to prevent online incidents. The findings have implications for (1) school policies about cyberbullying, (2) parent education about the risks associated with online communication, and (3) youth advice regarding strategies to prevent and deal with cyberbullying incidents.


Substantial cultures of Propionibacterium can be found in apparently aseptic shoulders revised three years or more after the index arthroplasty.
Revisions of apparently "aseptic" shoulder arthroplasties are not infrequently culture positive for Propionibacterium, organisms that may be introduced at the time of the index surgery when the dermal sebaceous glands are transected. This report seeks to answer the question, Do surgeons performing revision shoulder arthroplasty years after the index procedure need to be concerned about the persistence of Propionibacterium? We reviewed the medical records of 148 revision arthroplasties performed between July 2008 and June 2013 to find those revisions performed at least 3 years after the index procedure and at which intraoperative cultures were strongly positive for Propionibacterium. We identified 14 cases of revision surgery performed 8 ± 4 years after the original arthroplasty for which deep cultures were strongly positive for Propionibacterium. A total of 109 specimens were obtained, 84 of which were positive. All 14 patients were male. Shoulder arthroplasties revised for the mechanical problems of loosening or stiffness can be substantially culture positive for Propionibacterium, even if the revision is performed many years after the index procedure. Therefore, even in shoulder arthroplasties revised for mechanical problems years after the index procedures, surgeons should consider submitting multiple deep specimens for specific Propionibacterium culture. In the presence of persistent Propionibacterium, surgeons should consider the need for directed surgical and medical treatment in their management of a failed arthroplasty.


Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine.
The incidence of hepatocellular carcinoma with nonalcoholic steatohepatitis is increasing, and its clinicopathological features are well established. Several animal models of nonalcoholic steatohepatitis have been developed to facilitate its study; however, few fully recapitulate all its clinical features, which include insulin resistance, inflammation, fibrosis, and carcinogenesis. Moreover, these models require a relatively long time to produce hepatocellular carcinoma reliably. The aim of this study was to develop a mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis that develops quickly and reflects all clinically relevant features. Three-week-old C57BL/6J male mice were fed either a standard diet (MF) or a choline-deficient, high-fat diet (HFCD). The mice in the MF + diethylnitrosamine (DEN) and HFCD + DEN groups received a one-time intraperitoneal injection of DEN at the start of the respective feeding protocols. The mice in the HFCD and HFCD + DEN groups developed obesity early in the experiment and insulin resistance after 12 weeks. Triglyceride levels peaked at 8 weeks for all four groups and decreased thereafter. Alanine aminotransferase levels increased every 4 weeks, with the HFCD and HFCD + DEN groups showing remarkably high levels; the HFCD + DEN group presented the highest incidence of nonalcoholic steatohepatitis. The levels of fibrosis and steatosis varied, but they tended to increase every 4 weeks in the HFCD and HFCD + DEN groups. Computed tomography scans indicated that all the HFCD + DEN mice developed hepatic tumors from 20 weeks, some of which were glutamine synthetase-positive. The nonalcoholic steatohepatitis-hepatocellular carcinoma model we describe here is simple to establish, results in rapid tumor formation, and recapitulates most of the key features of nonalcoholic steatohepatitis. It could therefore facilitate further studies of the development, oncogenic potential, diagnosis, and treatment of this condition.


3D multi-tissue printing for kidney transplantation.
The kidneys are among the most commonly transplanted organs in the world. Transplant patients, as a consequence of their kidney disease and other risk factors which make it difficult for the surgeon to perform vascular anastomosis during kidney transplantation, often have numerous arterial calcifications. The preoperative assessment for transplantation includes an abdominal and pelvic CT scan without contrast that allows for the mapping of atheromatous calcification. However, non-contrast enhanced CT is not optimal and the surgeon is obliged to palpate the arteries during the operation to choose the anatomical site of the vascular anastomosis. This technical note reports the development of a new technique of preoperative reproduction of atherosclerotic arteries, owing to advancements in 3D multi-tissue printing technology. We used scans of four patients with varying degrees of calcified atheroma to model and print their arteries for their pre-surgical planning.


A Social Neuroscience Perspective on Adolescent Risk-Taking.
This article proposes a framework for theory and research on risk-taking that is informed by developmental neuroscience. Two fundamental questions motivate this review. First, why does risk-taking increase between childhood and adolescence? Second, why does risk-taking decline between adolescence and adulthood? Risk-taking increases between childhood and adolescence as a result of changes around the time of puberty in the brain's socio-emotional system leading to increased reward-seeking, especially in the presence of peers, fueled mainly by a dramatic remodeling of the brain's dopaminergic system. Risk-taking declines between adolescence and adulthood because of changes in the brain's cognitive control system - changes which improve individuals' capacity for self-regulation. These changes occur across adolescence and young adulthood and are seen in structural and functional changes within the prefrontal cortex and its connections to other brain regions. The differing timetables of these changes make mid-adolescence a time of heightened vulnerability to risky and reckless behavior.


On the deposition of volatiles and semivolatiles from cigarette smoke aerosols: relative rates of transfer of nicotine and ammonia from particles to the gas phase.
The hypothesis that elevated levels of ammonia-releasing compounds in tobacco and ammonia in mainstream (MS) smoke increase the rate and amount of nicotine evaporation from the particles of MS smoke aerosol was examined by kinetic modeling and experiments with MS cigarette smoke. Computational simulation of a kinetic mechanism describing volatile loss of nicotine, ammonia, and acetic acid from an aqueous solution was used to compute the time-dependent concentration of all species in the model. Because of the high volatility of ammonia relative to that of nicotine, variation over a wide range of initial ammonia concentration had no significant effect upon the rate of loss of nicotine from the model system. The effects of a variation in the volatile loss rate constant for ammonia and for the acid were examined. The simulations show that ammonia is lost from the model solution at a greater rate than nicotine and acid, and the loss of volatile acid has a significant role in the rate and amount of nicotine loss. Simulations with a model system undergoing a continuous steady addition of ammonia showed that high rates of ammonia addition could significantly increase the rate of nicotine volatile loss from the model solution. A series of smoking experiments was performed using blended cigarettes connected to a denuder tube. Deposition of smoke constituents can occur directly from the gas phase and by the deposition of smoke aerosol particles themselves. As nicotine exists >99% in the particle phase of MS smoke, in the absence of particle deposition, denuder tube deposition of nicotine occurs via the evaporation-deposition pathway. Solanesol, a nonvolatile tobacco and smoke terpene, was used to quantify the amount of particle deposition onto the denuder tube. The amount of ammonia deposited on the denuder tube was an order of magnitude greater than that of nicotine, showing that ammonia evaporates from the MS smoke particles much faster than does nicotine. The experimental results were supported and explained by the aqueous model simulations. Included in these experiments are cigarettes that differ in their MS smoke ammonia content by a factor of ca. five. However, an increased amount of MS smoke ammonia does not increase the rate of nicotine loss from the particles. The combined results support the conclusion that ammonia in mainstream smoke has little effect, if any, upon the rate and amount of nicotine evaporation from MS smoke particles.


Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation.
The phosphoinositide3-kinase (PI3K)/Akt and downstream mammalian target of rapamycin complex 1 (mTORC1) signalling cascades promote normal growth and are frequently hyperactivated in tumour cells. mTORC1 is also regulated by local nutrients, particularly amino acids, but the mechanisms involved are poorly understood. Unexpectedly, members of the proton-assisted amino-acid transporter (PAT or SLC36) family emerged from in vivo genetic screens in Drosophila as transporters with uniquely potent effects on mTORC1-mediated growth. In this study, we show the two human PATs that are widely expressed in normal tissues and cancer cell lines, namely PAT1 and PAT4, behave similarly to fly PATs when expressed in Drosophila. Small interfering RNA knockdown shows that these molecules are required for the activation of mTORC1 targets and for proliferation in human MCF-7 breast cancer and HEK-293 embryonic kidney cell lines. Furthermore, activation of mTORC1 in starved HEK-293 cells stimulated by amino acids requires PAT1 and PAT4, and is elevated in PAT1-overexpressing cells. Importantly, in HEK-293 cells, PAT1 is highly concentrated in intracellular compartments, including endosomes, wherein mTOR shuttles upon amino-acid stimulation. Therefore our data are consistent with a model in which PATs modulate the activity of mTORC1 not by transporting amino acids into the cell but by modulating the intracellular response to amino acids.


Effects of chronic renal failure on protein synthesis and albumin messenger ribonucleic acid in rat liver.
Previously we reported that chronic renal failure in rats leads to preferential disaggregation of liver membrane-bound polysomes associated with a decrease in albumin synthesis. To determine whether reduced albumin synthesis results from reduced cellular levels of albumin messenger RNA (mRNA) or some other molecular mechanism, we have employed mRNA-DNA hybridization in conjunction with cell-free protein synthesis to determine albumin mRNA sequence content and biological activity in subcellular fractions from control and uremic rat liver. Using high specific activity albumin [3H]-complementary DNA prepared from purified-albumin mRNA, we found that total liver polysomes and albumin mRNA sequence content are increased in uremic animals. The extra polysomes are located within the membrane-bound subcellular fraction. These polysomes, however, have reduced ability to synthesize albumin in the cell-free system, and mRNA isolated from membrane-bound polysomes of uremic liver showed reduced albumin synthesis. Evaluation of albumin mRNA size by hybridization analysis revealed a reduced content of intact albumin mRNA molecules per microgram of RNA in the liver of uremic animals. This was associated with increased ribonuclease activity in uremic cytosol. The diminished albumin synthesis by membrane-bound polysomes of uremic rat liver can, therefore, be explained by enhanced degradation of albumin mRNA.


Virucidal activity of oriental hornet Vespa orientalis venom against hepatitis C virus.
Hepatitis C virus (HCV) infection is a major worldwide health problem that can cause liver fibrosis and hepatocellular carcinoma (HCC). The clinical treatment of HCV infection mainly relies on the use of direct-acting antivirals (DAAs) that are usually expensive and have side effects. Therefore, achieving the discovery of more successful agents is always urgent. In this context, antiviral compounds that inhibit viral infections and disease progression with important therapeutic activities have been identified in animal venoms including arthropod toxins. This indicates that arthropod venoms represent a good natural source of promising candidates for new antivirals. The antiviral activity of the wasp venom (WV), isolated from the Oriental hornet (Vespa orientalis), was assessed using cell culture technique with human hepatocellular carcinoma-derived cell line (Huh7it-1) and the recombinant strain of HCV genotype 2a (JFH1). The results revealed that WV inhibited HCV infectivity with 50% inhibitory concentration (IC50) of 10 ng/mL, while the 50% cytotoxic concentration (CC50) was 11,000 ng/mL. Time of addition experiment showed that the WV blocked HCV attachment/entry to the cells probably through virucidal effect. On the other hand, the venom showed no inhibitory effect on HCV replication. WV can inhibit the entry stage of HCV infection at non-cytotoxic concentrations. Therefore, it could be considered a potential candidate for characterization of natural anti-HCV agents targeting the entry step.


Understanding forearm fractures in young children: Abuse or not abuse?
This retrospective study describes the characteristics and mechanisms of forearm fractures in children <18 months adding to the evidence-base about forearm fractures. It also examines which features of forearm fractures in young children may help discriminate between abusive and noninflicted injuries. Electronic medical records were reviewed for eligible patients evaluated between September 1, 2007 and January 1, 2012 at two children's hospitals in Chicago, IL. The main outcome measures were the type of fracture and the etiology of the fracture (abuse versus not abuse). The 135 included patients sustained 216 forearm fractures. Most were buckle (57%) or transverse (26%). Child protection teams evaluated 47 (35%) of the patients and diagnosed 11 (23%) as having fractures caused by abuse. Children with abusive versus non-inflicted injuries had significant differences in age (median age 7 versus 12 months), race, and presence of additional injuries. Children with abusive forearm fractures often presented without an explanation or a changing history for the injury. Children with non-inflicted forearm fractures often presented after a fall. No particular type of forearm fracture was specific for child abuse. Any forearm fracture in a young child should be evaluated with special attention to the details of the history and the presence of other injuries. Young age, additional injuries, and an absent or inconsistent explanation should increase concern that the fracture was caused by child abuse.


The (non)malignancy of cancerous amino acidic substitutions.
The process of natural selection acts both on individual organisms within a population and on individual cells within an organism as they develop into cancer. In this work, we have taken a first step toward understanding the differences in selection pressures exerted on the human genome under these disparate circumstances. Focusing on single amino acid substitutions, we have found that cancer-related mutations (CRMs) are frequent in evolutionarily conserved sites, whereas single amino acid polymorphisms (SAPs) tend to appear in sites having a more relaxed evolutionary pressure. Those CRMs classed as cancer driver mutations show greater enrichment for conserved sites than passenger mutations. Consistent with this, driver mutations are enriched for sites annotated as key functional residues and their neighbors, and are more likely to be located on the surface of proteins than expected by chance. Overall the pattern of CRM and polymorphism is remarkably similar, but we do see a clear signal indicative of diversifying selection for disruptive amino acid substitutions in the cancer driver mutations. The ultimate consequence of the appearance of those mutations must be advantageous for the tumor cell, leading to cell population-growth and migration events similar to those seen in natural ecosystems.


Statistical Optimisation of Phenol Degradation and Pathway Identification through Whole Genome Sequencing of the Cold-Adapted Antarctic Bacterium, Rhodococcus sp. Strain AQ5-07.
Study of the potential of Antarctic microorganisms for use in bioremediation is of increasing interest due to their adaptations to harsh environmental conditions and their metabolic potential in removing a wide variety of organic pollutants at low temperature. In this study, the psychrotolerant bacterium Rhodococcus sp. strain AQ5-07, originally isolated from soil from King George Island (South Shetland Islands, maritime Antarctic), was found to be capable of utilizing phenol as sole carbon and energy source. The bacterium achieved 92.91% degradation of 0.5 g/L phenol under conditions predicted by response surface methodology (RSM) within 84 h at 14.8 °C, pH 7.05, and 0.41 g/L ammonium sulphate. The assembled draft genome sequence (6.75 Mbp) of strain AQ5-07 was obtained through whole genome sequencing (WGS) using the Illumina Hiseq platform. The genome analysis identified a complete gene cluster containing catA, catB, catC, catR, pheR, pheA2, and pheA1. The genome harbours the complete enzyme systems required for phenol and catechol degradation while suggesting phenol degradation occurs via the β-ketoadipate pathway. Enzymatic assay using cell-free crude extract revealed catechol 1,2-dioxygenase activity while no catechol 2,3-dioxygenase activity was detected, supporting this suggestion. The genomic sequence data provide information on gene candidates responsible for phenol and catechol degradation by indigenous Antarctic bacteria and contribute to knowledge of microbial aromatic metabolism and genetic biodiversity in Antarctica.


Volar versus dorsal plating in the management of intra-articular distal radius fractures.
To compare the complications and functional and radiographic outcomes of volar and dorsal plating of intra-articular distal radius fractures. This retrospective review included 34 patients found by searching a database of 350 patients treated for distal radius fractures. Inclusion criteria were (1) at least 1 year of follow-up data and (2) open reduction and internal fixation of a multifragmentary fragment intra-articular distal radius fracture with either a nonlocking volar or dorsal plate. Twenty patients were treated with a dorsal plate and 14 patients were treated with a volar nonlocking plate. Objective and subjective outcome parameters were compared between the 2 groups. Objective evaluations included wrist range of motion, grip strength, and preoperative and postoperative radiographic parameters (radial inclination, palmar tilt, ulnar variance, fracture pattern). Subjective evaluations were performed using the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire score and the Gartland and Werley score. Volar plating resulted in a significantly better Gartland-Werley score compared with dorsal plating. There were no significant differences in the DASH score. Volar collapse was documented in 5 of the 20 patients in the dorsal plating group, which resulted in a mild loss of pronation compared with the volar plating group. No collapse occurred in the volar plating group. In addition the difference in the percentage of wrist range of motion compared with the contralateral wrist was not significant. Dorsal plating was associated with a ruptured extensor indicis tendon in 1 patient; secondary surgical procedures were required in 4 patients (tenolyses and radial styloidectomy). Volar plating was associated with median nerve neuropathy in 2 patients and intersection syndrome in one. Although both groups of patients had similar DASH scores the functional outcome in terms of Gartland and Werley scores was better in the volar plating group. In addition there was a higher rate of volar collapse and late complications in the dorsal plating group compared with the volar plating group. Therapeutic, Level III.


NMR structural studies of the first catalytic half-domain of ubiquitin activating enzyme.
We report a high resolution NMR structure and (15)N relaxation studies of the first catalytic cysteine half-domain (FCCH) of the mouse ubiquitin-activating enzyme E1, together with interaction studies of FCCH and the other catalytic E1 subdomain - SCCH (second catalytic cysteine half-domain). In solution, mouse FCCH forms a well-defined six-stranded antiparallel β-barrel structure, a common fold for many proteins with a variety of cellular functions. (15)N relaxation data reveal FCCH complex backbone dynamics and indicate which residues experience slow intramolecular motions. Some of these residues make contacts with the polar face of ubiquitin in the co-crystal structure of yeast E1 and ubiquitin. However, the titration of FCCH with ubiquitin does not show any visible chemical shift changes in the 2D (1)H/(15)N HSQC spectra of the FCCH. The 2D (1)H/(15)N HSQC experiments performed both for each catalytic half-domain individually and for their equimolar mixture in the milimolar concentration range display no detectable chemical shift perturbation, suggesting a lack of interaction between the two subdomains unless they are covalently linked via the adenylation domain.


Glucoreceptor mechanisms and the control of insulin release and biosynthesis.
The models proposed for the means whereby the B-cell recognises glucose and related compounds as signals for insulin release and biosynthesis are discussed. The observed correlations between rates of metabolism and insulin release and biosynthesis are consistent with the substrate-site hypothesis. For glucose itself, the enzymes catalysing the phosphorylation of the sugar provide an explanation for the major characteristics of the islet responses, but for N-acetylglucosamine evidence is presented that the sugar transport system fulfils this discriminatory role. Possible mechanisms whereby sugar metabolism may be linked to changes in Ca2+-handling are considered and evidence is given supporting a role for the cytosolic NADPH/NADP+ ratio and the islet content of phosphoenolpyruvate. The nature of the targets for cyclic AMP and Ca2+ is discussed and some properties of islet cAMP-dependent protein kinase are summarised. Evidence is presented for the presence of calmodulin in islets and the possible involvement of calmodulin in stimulus-secretion coupling. On the basis of these considerations a speculative hypothesis for the mechanisms involved in the B-cell responses to glucose is outlined.


Knowledge of scientific misconduct in publication among medical students.
Publication is a central element in research dissemination and scientific misconduct in publication is relatively ignored in biomedical research. This study is to assess the knowledge of scientific misconduct in publication among private and public sector medical students. A questionnaire-based cross-sectional study was carried in four (two public and two private) medical colleges of Karachi in 2015. After ethical approval, data were collected through convenient sampling and analyzed in SPSS 16.0. Descriptive statistics was used to summarize the data and Chi-square test was used for cross tabulation with sex, type of medical colleges, and knowledge of scientific misconduct in publication. A total of 592 medical students participated with mean age of 22.2 ± 1.47 years. The majority (491, 79%) of medical students had heard about the word "publication ethics," higher among public sector students than from private sector (P < 0.001). Only 78 (13.2%) reported to had published original articles, and 64 (10.8%) and 53 (9%) medical students had heard of "ICMJE authorship criteria" and "COPE," respectively. Knowledge about fabrication of data and scientific misconduct in publication was found to be statistically significant (P < 0.05) among males than female students. Statistically significant differences were also observed between public and private medical students for knowledge regarding salami slicing, ghost author, fabrication, and photomanipulation (P < 0.001) and for plagiarism (P < 0.005). Participants from public sector colleges scored significantly better in all above variables than private medical colleges except knowledge about salami slicing in which participants from latter performed significantly better than public sector students. The study demonstrates deficiencies in knowledge regarding several aspects of publication ethics among medical students of both public and private medical colleges in Karachi. There is a need to increase the awareness of research and publication ethics among students during their academic years.


Highly diverged novel subunit composition of apicomplexan F-type ATP synthase identified from Toxoplasma gondii.
The mitochondrial F-type ATP synthase, a multisubunit nanomotor, is critical for maintaining cellular ATP levels. In T. gondii and other apicomplexan parasites, many subunit components necessary for proper assembly and functioning of this enzyme appear to be missing. Here, we report the identification of 20 novel subunits of T. gondii F-type ATP synthase from mass spectrometry analysis of partially purified monomeric (approximately 600 kDa) and dimeric (>1 MDa) forms of the enzyme. Despite extreme sequence diversification, key FO subunits a, b, and d can be identified from conserved structural features. Orthologs for these proteins are restricted to apicomplexan, chromerid, and dinoflagellate species. Interestingly, their absence in ciliates indicates a major diversion, with respect to subunit composition of this enzyme, within the alveolate clade. Discovery of these highly diversified novel components of the apicomplexan F-type ATP synthase complex could facilitate the development of novel antiparasitic agents. Structural and functional characterization of this unusual enzyme complex will advance our fundamental understanding of energy metabolism in apicomplexan species.


ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA.
Mammals have nine different homologues (ALKBH1-9) of the Escherichia coli DNA repair demethylase AlkB. ALKBH2 is a genuine DNA repair enzyme, but the in vivo function of the other ALKBH proteins has remained elusive. It was recently shown that ALKBH8 contains an additional transfer RNA (tRNA) methyltransferase domain, which generates the wobble nucleoside 5-methoxycarbonylmethyluridine (mcm(5)U) from its precursor 5-carboxymethyluridine (cm(5)U). In this study, we report that (R)- and 5-methoxycarbonylhydroxymethyluridine (mchm(5)U), hydroxylated forms of mcm(5)U, are present in mammalian tRNA-Arg(UCG), and tRNA-Gly(UCC), respectively, representing the first example of a diastereomeric pair of modified RNA nucleosides. Through in vitro and in vivo studies, we show that both diastereomers of mchm(5)U are generated from mcm(5)U, and that the AlkB domain of ALKBH8 specifically hydroxylates mcm(5)U into (S)-mchm(5)U in tRNA-Gly(UCC). These findings expand the function of the ALKBH oxygenases beyond nucleic acid repair and increase the current knowledge on mammalian wobble uridine modifications and their biogenesis.


Risk and benefit of dual antiplatelet treatment among non-revascularized myocardial infarction patients in different age groups.
Dual anti-platelet treatment with clopidogrel and aspirin is indicated for most patients after myocardial infarction. We examined the risk/benefit relationship of dual anti-platelet treatment according to age in a nationwide cohort of 30,532 myocardial infarction patients without revascularization. Patients admitted with first-time myocardial infarction in 2002-2010, not undergoing revascularization, were identified from nationwide Danish registers. Dual anti-platelet treatment use was assessed by claimed prescriptions. Stratified into age groups, risk of bleeding, all-cause mortality and a combined endpoint of cardiovascular death, recurrent myocardial infarction and ischaemic stroke was analysed by Cox proportional-hazard models and tested in a propensity-score matched population. A total of 21,302 users and 9230 non-users of dual anti-platelet treatment were included (mean age 67.02 (±13.8) years and 64.7% males). Use of dual anti-platelet treatment decreased with age: 80% (<60 years), 76% (60-69 years), 66% (70-79 years) and 52% (>79 years). We found a reduced risk of cardiovascular death, recurrent myocardial infarction and ischaemic stroke in users <60 years (Hazard ratio (HR) =0.69; 95% confidence interval (CI) 0.59-0.80), 60-69 years (HR=0.64; 95% CI 0.56-0.73), 70-79 years (HR=0.80; 95% CI 0.72-0.89) and >79 years (HR=0.92; 95% CI 0.84-1.01, NS). Risk of bleeding increased with dual anti-platelet treatment use in patients aged <60 years (HR=1.63; 95% CI 1.17-2.26), 60-69 years (HR=1.22; 95% CI 0.97-1.59, NS), 70-79 years (HR=1.42; 95% CI 1.17-1.72) and >79 years (HR=1.46; 95% CI 1.22-1.74). Similar tendencies in all four age groups were found in the propensity-matched population. Dual anti-platelet treatment use was less likely among elderly patients although similar effects regarding both risk and benefit were found in all age groups. Increased focus on initiating dual anti-platelet treatment in elderly, non-invasively treated myocardial infarction patients is warranted.


Respiratory Health in Cleaners in Northern Europe: Is Susceptibility Established in Early Life?
There is some evidence that maternal smoking increases susceptibility to personal smoking's detrimental effects. One might question whether early life disadvantage might influence susceptibility to occupational exposure. In this cross-sectional study we investigated respiratory symptoms, asthma and self-reported chronic obstructive pulmonary disease (COPD) as related to working as a cleaner in Northern European populations, and whether early life factors influenced susceptibility to occupational cleaning's unhealthy effects. The RHINE III questionnaire study assessed occupational cleaning in 13,499 participants. Associations with respiratory symptoms, asthma and self-reported COPD were analysed with multiple logistic regressions, adjusting for sex, age, smoking, educational level, parent´s educational level, BMI and participating centre. Interaction of occupational cleaning with early life disadvantage (maternal smoking, severe respiratory infection <5 years, born during winter months, maternal age at birth >35 years) was investigated. Among 2138 ever-cleaners the risks of wheeze (OR 1.4, 95% CI 1.3-1.6), adult-onset asthma (1.5 [1.2-1.8]) and self-reported COPD (1.7 [1.3-2.2]) were increased. The risk increased with years in occupational cleaning (adult-onset asthma: ≤1 year 0.9 [0.7-1.3]; 1-4 years 1.5 [1.1-2.0]; ≥4 years 1.6 [1.2-2.1]). The association of wheeze with cleaning activity ≥4 years was significantly stronger for those with early life disadvantage than in those without (1.8 [1.5-2.3] vs. 1.3 [0.96-1.8]; pinteraction 0.035). Occupational cleaners had increased risk of asthma and self-reported COPD. Respiratory symptom risk was particularly increased in persons with factors suggestive of early life disadvantage. We hypothesize that early life disadvantage may increase airway vulnerability to harmful exposure from cleaning agents later in life.


The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism.
PGC-1α is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERRα and ERRγ) in the regulation of mitochondrial and metabolic gene networks. Dimerization of the ERRs is a pre-requisite for interactions with PGC-1α and other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) that PGC-1α binds in a strikingly different manner to ERRγ ligand-binding domains (LBDs) compared to its mode of binding to ERRα and other nuclear receptors (NRs), where it interacts directly with the two ERRγ homodimer subunits. Here, we show that PGC-1α receptor interacting domain (RID) binds in an almost identical manner to ERRα and ERRγ homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1α RID and ERR LBDs involve a single receptor subunit through high-affinity, ERR-specific L3 and low-affinity L2 interactions. NMR studies further defined the limits of PGC-1α RID that interacts with ERRs. Consistent with these findings, the solution structures of PGC-1α/ERRα LBDs and PGC-1α/ERRγ LBDs complexes share an identical architecture with an asymmetric binding of PGC-1α to homodimeric ERR. These studies provide the molecular determinants for the specificity of interactions between PGC-1α and the ERRs, whereby negative cooperativity prevails in the binding of the coactivators to these receptors. Our work indicates that allosteric regulation may be a general mechanism controlling the binding of the coactivators to homodimers.


Discrimination, family emotional climate, and African American health: An application of the BBFM.
The Biobehavioral Family Model (BBFM) is a biopsychosocial model of health that has been substantiated across multiple studies. However, the findings of those studies are limited given the lack of representation of Black/African American individuals in the samples. Discrimination is a chronic and pervasive stressor for many African American families, yet little is known about connections between discrimination, family relationships, and health. Using Data from the Midlife Development in the United States (MIDUS) Milwaukee project (n = 592), this study tested the pathways of the BBFM with a sample comprised only of African American individuals Additionally, it tested how discrimination influenced the pathways of the BBFM. Results of model testing found that family support (above and beyond romantic partner relationship quality and family strain) was a key factor in respondents' mental and physical health and that family support mediated the association between discrimination and mental health. The findings suggest the importance of including discrimination when examining family health pathways for African Americans and exploring the influence of relationships beyond the romantic partnership when examining health. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer.
The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. Disruption of TFAM results in heart failure and premature aging in mice. But very little is known about the role of TFAM in cancer development. Here, we report the identification of frequent frameshift mutations in the coding mononucleotide repeat of TFAM in sporadic colorectal cancer (CRC) cell lines and in primary tumors with microsatellite instability (MSI), but not in microsatellite stable (MSS) CRC cell lines and tumors. The presence of the TFAM truncating mutation, in CRC cells with MSI, reduced the TFAM protein level in vivo and in vitro and correlated with mtDNA depletion. Furthermore, forced overexpression of wild-type TFAM in RKO cells carrying a TFAM truncating mutation suppressed cell proliferation and inhibited RKO cell-induced xenograft tumor growth. Moreover, these cells showed more susceptibility to cisplatin-induced apoptosis due to an increase of cytochrome b (Cyt b) expression and its release from mitochondria. An interaction assay between TFAM and the heavy-strand promoter (HSP) of mitochondria revealed that mutant TFAM exhibited reduced binding to HSP, leading to reduction in Cyt b transcription. Collectively, these data provide evidence that a high incidence of TFAM truncating mutations leads to mitochondrial copy number reduction and mitochondrial instability, distinguishing most CRC with MSI from MSS CRC. These mutations may play an important role in tumorigenesis and cisplatin-induced apoptotic resistance of most microsatellite-unstable CRCs.


Dimethyl fumarate alters B-cell memory and cytokine production in MS patients.
We evaluated the effect of dimethyl fumarate (DMF) treatment on B-cell memory and cytokine production in 18 patients with relapsing remitting multiple sclerosis (RRMS) using peripheral blood mononuclear cells obtained prior to and at 6 months post-DMF initiation. We noted a decline in the absolute B-cell number with DMF treatment, with a preferential depletion of memory B cells and a concurrent increase in naïve B cells. We noted significant reductions in GM-CSF, TNF-α, and IL-6 producing B cells with DMF treatment. These effects on the B-cell compartment may underlie the beneficial effects of DMF in RRMS.


Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.


Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.
Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential biomarker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA. We measured serum concentrations of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters (N = 84) and office workers (N = 79) who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length. Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (β (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis (1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis (2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (- 0.14(- 0.28, - 0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and concentrations of exposure between the two groups and/or potential unmeasured confounding. Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.


Feasibility study of nanoscaled optical waveguide based on near-resonant surface plasmon polariton.
Currently subwavelength surface plasmon polariton (SPP) waveguides under intensive theoretical and experimental studies are mostly based on the geometrical singularity property of such waveguides. Typical examples include the metal-insulator-metal based waveguide and the metallic fiber. Both types of waveguides support a mode with divergent propagation constant as the waveguides' geometry (metal gap distance or fiber radius) shrinks to zero. Here we study an alternative way of achieving subwavelength confinement through deploying two materials with close but opposite epsilon values. The interface between such two materials supports a near-resonant SPP. By examining the relationship between mode propagation loss and the mode field size for both planar and fiber waveguides, we show that waveguides based on near-resonant SPP can be as attractive as those solely based on geometrical tailoring. We then explicitly study a silver and silicon based waveguide with a 25nm core size at 600nm wavelength, in its properties like single-mode condition, mode loss and group velocity. It is shown that loss values of both materials have to be decreased by approximately 1000 times in order to have 1dB/microm propagation loss. Hence we point out the necessity of novel engineering of low-loss metamaterials, or introducing gain, for practical applications of such waveguides. Due to the relatively simple geometry, the proposed near-resonant SPP waveguides can be a potential candidate for building optical circuits with a density close to the electronic counterpart.


Improved intraoperative management of anastomotic bleeding during aortic reconstruction: results of a randomized controlled trial.
In a randomized controlled trial, the effectiveness of a polymeric surgical sealant (CoSeal) was compared to Gelfoam/thrombin for managing anastomotic bleeding after implantation of Dacron grafts during aortic reconstruction for nonruptured aneurysms. Each treatment was directly applied to the suture line after confirmation of anastomotic bleeding. The proportion of suture line sites that achieved immediate sealing and the proportion sealed within 5 minutes were determined among 37 experimental (59 sites) and 17 control subjects (27 sites). A significantly greater proportion of bleeding suture line sites treated with the polymeric sealant achieved immediate sealing following reestablishment of blood flow compared with control-treated sites [48 of 59 (81%) vs 10 of 27 (37%); P = 0.002]. The difference between treatment groups was maintained after 5 minutes with approximately 85 per cent (50 of 59) of CoSeal sites compared to just over one-half (14 of 27) of control sites demonstrating ultimate sealing (P = 0.01). There were no adverse events related to the use of the polymeric sealant in this study. These results support the use of this novel sealant for the intraoperative management of anastomotic bleeding during aortic reconstruction procedures.


Genomic characterization of Nocardia seriolae strains isolated from diseased fish.
Members of the genus Nocardia are widespread in diverse environments; a wide range of Nocardia species are known to cause nocardiosis in several animals, including cat, dog, fish, and humans. Of the pathogenic Nocardia species, N. seriolae is known to cause disease in cultured fish, resulting in major economic loss. We isolated two N. seriolae strains, CK-14008 and EM15050, from diseased fish and sequenced their genomes using the PacBio sequencing platform. To identify their genomic features, we compared their genomes with those of other Nocardia species. Phylogenetic analysis showed that N. seriolae shares a common ancestor with a putative human pathogenic Nocardia species. Moreover, N. seriolae strains were phylogenetically divided into four clusters according to host fish families. Through genome comparison, we observed that the putative pathogenic Nocardia strains had additional genes for iron acquisition. Dozens of antibiotic resistance genes were detected in the genomes of N. seriolae strains; most of the antibiotics were involved in the inhibition of the biosynthesis of proteins or cell walls. Our results demonstrated the virulence features and antibiotic resistance of fish pathogenic N. seriolae strains at the genomic level. These results may be useful to develop strategies for the prevention of fish nocardiosis.


Changes in brown eggshell color as the hen ages.
The color of eggshells from eggs laid by commercial-type Hy-Line brown hens 25 wk of age was studied over a period of 10 mo. Color measurements were made by a color machine vision system and were analyzed using a mixed model to calculate between and within hen variances and to investigate the effect of time on shell color. Hens laid eggs with lighter colored shells as the flock aged, as evidenced by the lightness (L*) values increasing in time. A decrease in pigmentation was associated with a decrease in the amount of redness (a*) in the eggshell. When L* and a* values were corrected for egg weight, the rate of change in the L* and a* values decreased, indicating that size of the egg was a major factor affecting the color of the eggshell. These findings quantified the observations that older hens lay lighter colored eggs due to an increase in egg size associated with no proportionate change in the quantity of pigment deposited over the shell surface. Using a 2-stage sampling analysis and the variances between and within hens, sample sizes required to estimate the color of eggshells within 5% of the true mean were calculated. Accordingly, 11 eggs would need to be collected from each of the 51 hens housed for a study of brown eggshell color using the L*, a*, and b* (yellowness) coordinates.


First endoluminal system for transmural resection of colorectal tissue with a prototype full-thickness resection device in a porcine model.
Endoluminal transmural resection of colorectal lesions is a pivotal advance in endoscopic technology. A full-thickness resection device has been developed that functions through a combination of tissue grasping, stapling, and cutting under endoscopic guidance. This preclinical study evaluated the performance, safety, and effectiveness of the full-thickness resection device in a porcine model. The full-thickness resection device consists of an operative handle, flexible shaft, and a resection chamber head. Eight pigs were randomized to 2 survival groups (4 each) of 14 and 28 days. The mucosa was marked electrosurgically to delineate target areas in the distal colon. A gastroscope inserted through the channel of the full-thickness resection device was advanced together with the device to the target. Targeted tissue was pulled into the resection chamber with a forceps, staples were deployed, and the isolated specimen was resected with a cutting blade. Histologic and radiographic evaluations were performed. All resections were transmural. Mean resected tissue diameter was 3.6 cm (1.4-5.2 cm). Mean procedure time was 30.2 (15) minutes. Minor mechanical problems required the use of replacement devices to complete 3 procedures. Resection sites were identified endoscopically and radiographically at sacrifice. In one animal, local adhesions were present. Histology evaluation disclosed resection line mucosal ulceration in 4 animals with fibroinflammatory changes consistent with healing. The full-thickness resection device can be used for endoluminal transmural localized resection of colorectal tissue in an animal model.


Involvement of the TPJ area in processing of novel global forms.
The neuropsychological syndrome "simultanagnosia" is characterized by the inability to integrate local elements into a global entity. This deficit in Gestalt perception is mainly apparent for novel global structures administered in clinical tests or unfamiliar visual scenes. Recognition of familiar complex objects or well-known visual scenes is often unaffected. Recent neuroimaging studies and reports from simultanagnosia patients suggest a crucial involvement of temporoparietal brain areas in processing of hierarchically organized visual material. In this study, we investigated the specific role of the TPJ in Gestalt perception. On the basis of perceptual characteristics known from simultanagnosia, we hypothesized that TPJ is dominantly involved in processing of novel object arrangements. To answer this question, we performed a learning study with hierarchical stimuli and tested behavioral and neuronal characteristics of Gestalt perception pre- and posttraining. The study included 16 psychophysical training sessions and two neuroimaging sessions. Participants improved their behavioral performance for trained global stimuli and showed limited transfer to untrained global material. We found significant training dependent neuronal signal modulations in anterior right hemispheric TPJ regions. These activation changes were specific to trained global stimuli, whereas no systematic neuronal response changes were observed for recognition of untrained global stimuli, local elements and regular objects that served as control stimuli. In line with perceptual characteristics in simultanagnosia, the results argue for an involvement of TPJ in processing of novel global structures. We discuss the signal modulations in the context of a more efficient or different neuronal strategy to process familiar global stimuli.


Effect and fate of orally administered lactic acid in rats.
We investigated the effect and the fate of an extremely high amount of orally administered lactic acid in rats. The dosed amount of lactic acid, 390 mg per 200 g body weight (30 times higher than that normally detected in the stomach of rats), was determined from the results of observation of acute toxicity of lactic acid in rats. Six hours after the administration of excess lactic acid together with 10 muCi of L-[U-14C]Lactic acid and 10 muCi of D-[U-14C]lactic acid, rats were sacrificed and the pH of the blood, the amount of lactic acid in each organ, L-lactate dehydrogenase (LDH) and some other enzyme activities and incorporation of radioactivities in each fraction of certain organs were measured. The control rats were given the labeled lactic acid and the same volume of water in place of cold lactic acid. Significant decrease of blood pH (delta- pH = 0.14) and increase of blood lactic acid concentration (2-fold) were observed. However, these differences were no longer observed at 24hr after the administration. The amount of lactic acid degraded to expired CO2 was 42.4% in the experimental group, whereas it was 61.3% in the control group. Radioactivities incorporated into protein and lipid fractions in the experimental group were higher than those in the control group, 3.8 and 4.9 times, respectively. It was suggested that an extremely high amount of orally administered lactic acid was utilized as an energy source, and that an excess of lactic acid was incorporated into protein and lipid in addition to degradation into CO2.


QF2011: a protocol to study the effects of the Queensland flood on pregnant women, their pregnancies, and their children's early development.
Retrospective studies suggest that maternal exposure to a severe stressor during pregnancy increases the fetus' risk for a variety of disorders in adulthood. Animal studies testing the fetal programming hypothesis find that maternal glucocorticoids pass through the placenta and alter fetal brain development, particularly the hypothalamic-pituitary-adrenal axis. However, there are no prospective studies of pregnant women exposed to a sudden-onset independent stressor that elucidate the biopsychosocial mechanisms responsible for the wide variety of consequences of prenatal stress seen in human offspring. The aim of the QF2011 Queensland Flood Study is to fill this gap, and to test the buffering effects of Midwifery Group Practice, a form of continuity of maternity care. In January 2011 Queensland, Australia had its worst flooding in 30 years. Simultaneously, researchers in Brisbane were collecting psychosocial data on pregnant women for a randomized control trial (the M@NGO Trial) comparing Midwifery Group Practice to standard care. We invited these and other pregnant women to participate in a prospective, longitudinal study of the effects of prenatal maternal stress from the floods on maternal, perinatal and early childhood outcomes. Data collection included assessment of objective hardship and subjective distress from the floods at recruitment and again 12 months post-flood. Biological samples included maternal bloods at 36 weeks pregnancy, umbilical cord, cord blood, and placental tissues at birth. Questionnaires assessing maternal and child outcomes were sent to women at 6 weeks and 6 months postpartum. The protocol includes assessments at 16 months, 2½ and 4 years. Outcomes include maternal psychopathology, and the child's cognitive, behavioral, motor and physical development. Additional biological samples include maternal and child DNA, as well as child testosterone, diurnal and reactive cortisol. This prenatal stress study is the first of its kind, and will fill important gaps in the literature. Analyses will determine the extent to which flood exposure influences the maternal biological stress response which may then affect the maternal-placental-fetal axis at the biological, biochemical, and molecular levels, altering fetal development and influencing outcomes in the offspring. The role of Midwifery Group Practice in moderating effects of maternal stress will be tested.


Analysis of six chloroplast genomes provides insight into the evolution of Chrysosplenium (Saxifragaceae).
Chrysosplenium L. (Saxifragaceae) is a genus of plants widely distributed in Northern Hemisphere and usually found in moist, shaded valleys and mountain slopes. This genus is ideal for studying plant adaptation to low light conditions. Although some progress has been made in the systematics and biogeography of Chrysosplenium, its chloroplast genome evolution remains to be investigated. To fill this gap, we sequenced the chloroplast genomes of six Chrysosplenium species and analyzed their genome structure, GC content, and nucleotide diversity. Moreover, we performed a phylogenetic analysis and calculated non-synonymous (Ka) /synonymous (Ks) substitution ratios using the combined protein-coding genes of 29 species within Saxifragales and two additional species as outgroups, as well as a pair-wise estimation for each gene within Chrysosplenium. Compared with the outgroups in Saxifragaceae, the six Chrysosplenium chloroplast genomes had lower GC contents; they also had conserved boundary regions and gene contents, as only the rpl32 gene was lost in four of the Chrysosplenium chloroplast genomes. Phylogenetic analyses suggested that the Chrysosplenium separated to two major clades (the opposite group and the alternate group). The selection pressure estimation (Ka/Ks ratios) of genes in the Chrysosplenium species showed that matK and ycf2 were subjected to positive selection. This study provides genetic resources for exploring the phylogeny of Chrysosplenium and sheds light on plant adaptation to low light conditions. The lower average GC content and the lacking gene of rpl32 indicated selective pressure in their unique habitats. Different from results previously reported, our selective pressure estimation suggested that the genes related to photosynthesis (such as ycf2) were under positive selection at sites in the coding region.


Participatory mapping of target areas to enable operational larval source management to suppress malaria vector mosquitoes in Dar es Salaam, Tanzania.
Half of the population of Africa will soon live in towns and cities where it can be protected from malaria by controlling aquatic stages of mosquitoes. Rigorous but affordable and scaleable methods for mapping and managing mosquito habitats are required to enable effective larval control in urban Africa. A simple community-based mapping procedure that requires no electronic devices in the field was developed to facilitate routine larval surveillance in Dar es Salaam, Tanzania. The mapping procedure included (1) community-based development of sketch maps and (2) verification of sketch maps through technical teams using laminated aerial photographs in the field which were later digitized and analysed using Geographical Information Systems (GIS). Three urban wards of Dar es Salaam were comprehensively mapped, covering an area of 16.8 km2. Over thirty percent of this area were not included in preliminary community-based sketch mapping, mostly because they were areas that do not appear on local government residential lists. The use of aerial photographs and basic GIS allowed rapid identification and inclusion of these key areas, as well as more equal distribution of the workload of malaria control field staff. The procedure developed enables complete coverage of targeted areas with larval control through comprehensive spatial coverage with community-derived sketch maps. The procedure is practical, affordable, and requires minimal technical skills. This approach can be readily integrated into malaria vector control programmes, scaled up to towns and cities all over Tanzania and adapted to urban settings elsewhere in Africa.


Criminality and Asbestos in Industry.
Criminal prosecutions of individuals in the asbestos industry are reviewed, particularly the case of asbestos owner-executive Stephan Schmidheiny. Italian courts sentenced Schmidheiny to sixteen to eighteen years in jail for creating an environmental disaster causing three thousand deaths. The convictions were overturned on a technicality, and a murder case against Schmidheiny has started. His firm, Eternit, made asbestos-cement building products in many countries. Schmidheiny directed a cover-up that the Italian Court of Appeal blamed for delaying the ban of asbestos in Italy by ten years. Today, the asbestos industry is a criminal industry, profiting only by minimizing its costs for the prevention and compensation of occupational and environmental illness. The asbestos industry should only be consulted by governments for the purpose of closing it and dealing with the legacy of in-place asbestos.


Stress memory induced rearrangements of HSP transcription, photosystem II photochemistry and metabolism of tall fescue (Festuca arundinacea Schreb.) in response to high-temperature stress.
When plants are pre-exposed to stress, they can produce some stable signals and physiological reactions that may be carried forward as "stress memory". However, there is insufficient information about plants' stress memory responses mechanisms. Here, two tall fescue genotypes, heat-tolerant PI 574522 and heat-sensitive PI 512315, were subjected to recurring high-temperature pre-acclimation treatment. Two heat shock protein (HSP) genes, LMW-HSP and HMW-HSP, exhibited transcriptional memory for their higher transcript abundance during one or more subsequent stresses (S2, S3, S4) relative to the first stress (S1), and basal transcript levels during the recovery states (R1, R2, and R3). Activated transcriptional memory from two trainable genes could persist up to 4 days, and induce higher thermotolerance in tall fescue. This was confirmed by greater turf quality and lower electrolyte leakage. Pre-acclimation treatment inhibited the decline at steps of O-J-I-P and energy transport fluxes in active Photosystem II reaction center (PSII RC) for both tall fescue genotypes. The heat stress memory was associated with major shifts in leaf metabolite profiles. Furthermore, there was an exclusive increase in leaf organic acids (citric acid, malic acid, tris phosphoric acid, threonic acid), sugars (sucrose, glucose, idose, allose, talose, glucoheptose, tagatose, psicose), amino acids (serine, proline, pyroglutamic acid, glycine, alanine), and one fatty acid (butanoic acid) in pre-acclimated plants. These observations involved in transcriptional memory, PSII RC energy transport and metabolite profiles could provide new insights into the plant high-temperature response process.


High prevalence of malnutrition both on hospital admission and predischarge.
In Dutch hospitals malnutrition screening is routinely performed at admission, but not during follow-up or before discharge. Therefore we evaluated nutritional status during hospitalization and predischarge in a routine care setting. The Patient-Generated Subjective Global Assessment (PG-SGA) was used to assess nutritional status (PG-SGA Categories: A = well nourished, B = moderate/suspected malnutrition, C = severely malnourished) in adult patients on four wards of a university hospital at admission, day 5, day 10, and day ≥15. Because data were obtained in the context of clinical routine, not all data points are available for all patients. Last assessment before discharge (within ≤4 d) was taken as predischarge measurement. PG-SGA data at admission were obtained in 584 patients (age 57.2 ± 17.3 y, 51.4% women, body mass index 27.0 ± 5.5 kg/m2). Prevalence of PG-SGA stage B/C was 31% at admission, 56% on day 5 (n = 292), 66% on day 10 (n = 101), and 79% on day ≥15 (n = 14). PG-SGA predischarge data were available in 537 patients, 36% of whom were PG-SGA stage B/C. Of the 91 patients assessed both at admission and predischarge, 30% of well-nourished patients became malnourished and 82% of malnourished patients remained so. Prevalence of malnutrition in hospitalized patients is high at admission (31%) and, importantly, also high predischarge (36%). Malnutrition is more prevalent in patients with a longer length of stay. These findings underscore the importance of follow-up of nutritional status in hospitalized patients and adequate transmural nutrition care after discharge to prevent malnutrition from remaining undetected and untreated.


The Fasting Hyperglycaemia Study: I. Subject identification and recruitment for a non-insulin-dependent diabetes prevention trial.
Subjects at increased risk for developing non-insulin-dependent diabetes mellitus (NIDDM) were encouraged via a public awareness campaign, general practitioners, or a direct approach (in the case of women with previous gestational diabetes) to attend one of three English and two French centers for fasting plasma glucose (FPG) measurement. Of 1,580 subjects (mean +/- SD age, 47 +/- 10 years), 29% were male, 56% had a diabetic relative, 20% had a history of elevated blood glucose or glycosuria, and 9% previously had gestational diabetes. Thirty-one percent (493) had an initial increased fasting glucose ([IFG] 5.5 to 7.7 mmol.L-1), 3% (41) a diabetic fasting glucose ([DFG] > or = 7.8 mmol.L-1), and 66% (1,046) a normal fasting glucose ([NFG] < 5.5 mmol.L-1). Four hundred forty-one of the 493 returned for a second FPG measurement, and 67% (293) of these had a similar value on repeat testing 2 weeks later. A 75-g, 2-hour oral glucose tolerance test (OGTT) in 223 of these subjects showed that 37% (83) had impaired glucose tolerance (IGT), 26% (58) diabetes mellitus (DM), and 37% (82) normal glucose tolerance (NGT). Seven percent of self-referred patients had NIDDM by World Health Organization (WHO) criteria. Eighty-eight percent of those with an initial DFG had an increased glycated hemoglobin (> 6.2%), and 75% an increased fructosamine (> 282 mumol.L-1). While these two glycemic measures provided good discrimination for diabetes, neither were reliable in detecting those with increased but not diabetic FPG values. In conclusion, 293 (19%) of 1,580 self-referred subjects were identified as having persistently increased FPG, and 227 have been entered into a randomized NIDDM prevention trial evaluating healthy-living advice and sulfonylurea therapy.


New methods of MR image intensity standardization via generalized scale.
Image intensity standardization is a post-acquisition processing operation designed for correcting acquisition-to-acquisition signal intensity variations (non-standardness) inherent in Magnetic Resonance (MR) images. While existing standardization methods based on histogram landmarks have been shown to produce a significant gain in the similarity of resulting image intensities, their weakness is that in some instances the same histogram-based landmark may represent one tissue, while in other cases it may represent different tissues. This is often true for diseased or abnormal patient studies in which significant changes in image intensity characteristics may occur. In an attempt to overcome this problem, in this paper, we present two new intensity standardization methods based on two scale concepts developed in Madabhushi et al. [Computer Vision Image Understanding 101, 100-121 (2006)] for image processing applications. These scale concepts are utilized in this paper to accurately determine principal tissue regions within MR images. Landmarks derived from these regions are used to perform intensity standardization. The new methods were qualitatively and quantitatively evaluated on a total of 67 clinical three dimensional (3D) MR images corresponding to four different protocols and to normal, Multiple Sclerosis (MS), and brain tumor patient studies. The new scale-based methods were found to be better than the existing methods, with a significant improvement observed for severely diseased and abnormal patient studies.


Dimension-specific signal modulation in visual search: evidence from inter-stimulus surround suppression.
A fundamental task for the visual system is to determine where to attend next. In general, attention is guided by visual saliency. Computational models suggest that saliency values are estimated through an iterative process in which each visual item suppresses each other item's saliency, especially for those with close proximity. To investigate this proposal, we tested the effect of two salient distractors on visual search for a size target. While fixing the target-to-distractor distance, we manipulated the distance between two distractors. If two salient distractors suppressed each other when they were close together, they should interfere with search less; this was exactly what we found. However, we observed such a distance effect only for distractors of the same dimension (e.g., both defined in color) but not for those of different dimensions (e.g., one defined in color and the other in shape), displaying specificity to a perceptual dimension. Therefore, we conclude that saliency in visual search is calculated through a surround suppression process that occurs at a dimension-specific level.


O6-methylguanine-induced cell death involves exonuclease 1 as well as DNA mismatch recognition in vivo.
Alkylation-induced O(6)-methylguanine (O(6)MeG) DNA lesions can be mutagenic or cytotoxic if unrepaired by the O(6)MeG-DNA methyltransferase (Mgmt) protein. O(6)MeG pairs with T during DNA replication, and if the O(6)MeG:T mismatch persists, a G:C to A:T transition mutation is fixed at the next replication cycle. O(6)MeG:T mismatch detection by MutSalpha and MutLalpha leads to apoptotic cell death, but the mechanism by which this occurs has been elusive. To explore how mismatch repair mediates O(6)MeG-dependent apoptosis, we used an Mgmt-null mouse model combined with either the Msh6-null mutant (defective in mismatch recognition) or the Exo1-null mutant (impaired in the excision step of mismatch repair). Mouse embryonic fibroblasts and bone marrow cells derived from Mgmt-null mice were much more alkylation-sensitive than wild type, as expected. However, ablation of either Msh6 or Exo1 function rendered these Mgmt-null cells just as resistant to alkylation-induced cytotoxicity as wild-type cells. Rapidly proliferating tissues in Mgmt-null mice (bone marrow, thymus, and spleen) are extremely sensitive to apoptosis induced by O(6)MeG-producing agents. Here, we show that ablation of either Msh6 or Exo1 function in the Mgmt-null mouse renders these rapidly proliferating tissues alkylation-resistant. However, whereas the Msh6 defect confers total alkylation resistance, the Exo1 defect leads to a variable tissue-specific alkylation resistance phenotype. Our results indicate that Exo1 plays an important role in the induction of apoptosis by unrepaired O(6)MeGs.


Astragaloside IV improves metabolic syndrome and endothelium dysfunction in fructose-fed rats.
The prevalence of metabolic syndrome has increased in modern society and the condition is proving to be a common precursor of cardiovascular disease. The aim of the present study was to investigate whether astragaloside IV, a major active constituent of Astragalus membranaceus (Fisch) Bge., is able to prevent the development of hypertension and endothelial dysfunction in fructose-fed rats. Rats were fed with 10% fructose in their drinking water for 8 weeks. From the beginning of week 5, two groups of fructose-fed rats were treated with 0.5 or 2 mg/kg, i.p., astragaloside IV. Another group of fructose-fed rats, injected with the same volume of vehicle (dimethylsulfoxide, DMSO) from week 5, served as the control group. At the end of the treatment period, blood pressure, blood glucose, glucose tolerance, blood insulin and lipids were determined. In addition, in vitro experiments were conducted at the end of the eight week treatment period to evaluate endothelium-dependent aortic vasorelaxation, as well as myocardial and aortic tissue levels of nitrate and nitrite (NOx) and cGMP. Fructose-fed rats developed clustering signs of metabolic syndrome, such as increased bodyweight, mild hypertension, hyperinsulinaemia, hypertriglyceridaemia, impaired glucose tolerance and impaired endothelium-dependent vasorelaxation. Administration of astragaloside IV reduced blood pressure and triglyceride levels in fructose-fed rats and high dose of astragaloside IV also improved glucose tolerance and endothelium-dependent vasorelaxation. The astragaloside IV-induced improvement in vasorelaxation was associated with increased levels of aortic NOx and cGMP and was abrogated by blockade of nitric oxide synthase with NG-nitro-l-arginine methyl ester (l-NAME). On the basis of its favourable effects on lipid metabolism, endothelium-dependent vasorelaxation and the nitric oxide-cGMP-related pathway, astragaloside IV may be useful in ameliorating food-induced metabolic syndrome.


Schizotypal Personality Questionnaire-Brief: factor structure and convergent validity in inpatient adolescents.
We examined the internal consistency, factor structure, and validity of the Schizotypal Personality Questionnaire-Brief (SPQ-B). Two hundred thirty-seven psychiatrically hospitalized adolescents were administered the SPQ-B and a battery of well-established self-report instruments. The SPQ-B demonstrated adequate internal consistency. Exploratory factor analysis provided mixed support for the SPQ-B 3-factor structure of interpersonal deficits, cognitive-perceptual deficits, and disorganization. The Interpersonal and Cognitive-Perceptual subscales demonstrated convergent and discriminant relationships with other measures of interpersonal impairment and cognitive abnormalities. We concluded that the SPQ-B is a promising measure for evaluating schizotypal personality disorder features, specifically interpersonal and cognitive-perceptual deficits, with adolescent psychiatric inpatients.


Understanding the professional socialization of canadian physical therapy students: a qualitative investigation.
To understand the professional socialization of physical therapy (PT) students. Forty-two students enrolled in our newly developed master's degree programme wrote three-page reflective journals on a critical learning incident after each of three selected clinical experiences. The journals were coded and analyzed, and major themes were identified and described. A separate cohort of 44 students participated in focus groups after the same three clinical experiences to check the trustworthiness of the results. Following the first placement, the main themes coded were emotions, self-confidence, professionalism in the real world, communication, and learning by doing. After the intermediate placement, major themes were idealism versus realism, depth of communication with clients, and breadth of communication with family members and colleagues. Aspects of clinical learning were variable, and self-confidence remained an issue. After the final placement, most students were deeply engaged with their clients and self-confidence had developed to the point of self-efficacy. Tensions increased between the concept of ideal practice and the pragmatics of actual practice, and the concept of self as protégé (rather than as object of the supervisor's evaluation) emerged. The themes were subsequently assembled in a booklet with representative quotations. These results contribute to foundational knowledge required by PT educators, including clinical instructors, by explicitly describing the professional socialization of PT students.